FD-895 was the first member of a family of 12-membered macrolides identified with potent cytotstatic activity in select tumor cell lines during hypoxia response. FD-895 is shown to inhibit the proliferation of tumor cell growth by altering natural gene splicing. FD-895 has IC50 value of 24.2±0.9 nM and has been reported to have hydrolytic instability. Additional studies have led to the isolation of a family of related macrolides including pladienolides. The early suspension of clinical trials for such compounds has created a need for new cancer therapies.
Chronic lymphocytic leukemia (CLL), one of the most common types of leukemia, characterized by an abnormal population of B lymphocytes in the blood that display a unique but characteristic pattern of cell surface markers such as the atypical co-production of CD5 and CD23. Despite the recent advance of combination treatments such as FCR (fludarabine, cyclophosphamide and rituximab) that confers a survival advantage, there is still no cure for CLL. Additionally, high-risk CLL groups such as patients with 17p deletion have a worse diagnosis and often fail to respond to therapy. Given these complications, there is an immediate need for agents that act on CLL through novel pathways.
Splicing, the removal of introns and joining of exons from nascent pre-mRNA, has recently gained attention as a target for cancer given the distinct splicing patterns identified both in tumor cell and metastatic tumor populations. Recently, a series of studies identified heterozygous missense mutations in U2AF1 and SF3B1 genes associated with myelodysplastic syndrome (MDS), and SF3B1 is frequently mutated in both MDS and chronic lymphocytic leukemia (CLL). Splicing plays an important role in human biology and its relevance in cancer is rapidly emerging. Recent advances in oligonucleotide sequencing demonstrate that alternative splicing and gene mutations involved in the spliceosome system can have a role in tumorigenesis and confer clinical prognosis in haematologic diseases including chronic lymphocytic leukemia (CLL). However, there are few, if any, well-defined molecular probes that can be used to monitor splicing events the role of the spliceosome system, as a molecular target in cancer has not been completely defined. Thus, the identification of selective and potent derivatives of macrolides like FD-895 with enhanced efficacy is of crucial and significant value. Provided herein are solutions to these and other problems in the art.